Chromosomal rearrangements are commonly associated with AML. The translocation t(8;21)
is the most common rearrangement, found in 10 – 15% of AML and generates the RUNX1/ETO
(AML1/ETO, RUNX1/RUNX1T1) fusion protein. A dynamic equilibrium between RUNX1 and
RUNX1/ETO binding is required for maintaining the leukaemic phenotype. In spite of
being a transcriptional repressor, RNAi experiments identified many direct RUNX1/ETO
target genes that are upregulated by this fusion protein including DUPS6 and PTK2.
PTK2 encodes the Focal Adhesion Kinase (FAK) which regulates cell proliferation and
migration. DUSP6 (MKP3) also mediates cellular proliferation and differentiation by
negatively regulating members of the mitogen-activated protein (MAP) kinase family
(ERK2, JNK, p38).
Preliminary data show DUSP6 is indispensable in the propagation and self-renewal of
AML cells, as shown in proliferation and clonogenicity assays of cells incubated with
and without the DUSP6 inhibitor (E/Z)-BCI. shRNA mediated knockdown will be used to
determine DUSP6 requirement, and will underline the impact of this protein, in AML.
